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A Synbiotic Mixture Augmented the Efficacy of Doxepin, Venlafaxine

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A Synbiotic Mixture Augmented the Efficacy of Doxepin, Venlafaxine Turk J Pharm Sci 2020;17(3):293-298 DOI: 10.4274/tjps.galenos.2019.94210 ORIGINAL ARTICLE A Synbiotic Mixture Augmented the Efficacy of Doxepin, Venlafaxine, and Fluvoxamine in a Mouse Model of Depression Sinbiyotik Karışım, Fare Depresyon Modelinde Doksepin, Venlafaksin ve Fluvoksaminin Etkinliğini Artırdı Azadeh MESRIPOUR1*, Andiya MESHKATI1, Valiollah HAJHASHEMI2 1Isfahan University of Medical Sciences, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Toxicology, Isfahan, Iran 2Isfahan University of Medical Sciences, School of Pharmacy and Pharmaceutical Sciences, Isfahan Pharmaceutical Sciences Research Center, Isfahan, Iran ABSTRACT Objectives: Currently available antidepressant drugs have notable downsides; in addition to their side effects and slow onset of action their moderate efficacy in some individuals may influence compliance. Previous literature has shown that probiotics may have antidepressant effects. Introducing complementary medicine in order to augment the efficacy of therapeutic doses of antidepressant drugs appears to be very important. Therefore, the effect of adding a synbiotic mixture to drinking water was assessed in a mouse model of depression following the administration of three antidepressant drugs belonging to different classes. Materials and Methods: The marble burying test (MBT) and forced swimming test (FST) were used as animal models of obsessive behavior and despair. The synbiotic mixture was administered to the mice’s drinking water (6.25x106 CFU) for 14 days and the tests were performed 30 min after the injection of the lowest dose of doxepin (1 mg/kg), venlafaxine (15 mg/kg), and fluvoxamine (15 mg/kg) on days 7 and 14. Results: After 7 days of ingestion of the synbiotic mixture, immobility time decreased in the FST for doxepin (92±5.5 s) and venlafaxine (17.3±2.5 s) compared to the control group (drinking water), but fluvoxamine decreased immobility time after 14 days of ingestion of the synbiotic mixture (70±7.5 s). Preadministration of the synbiotic mixture improved the MBT test response for venlafaxine, while it did not change the results for the other two drugs. Conclusion: Adding the synbiotic mixture to drinking water improved the efficacy of discrete antidepressant drugs particularly during the FST. Probiotics could be a useful complementary medicine for drug-resistant depressed individuals. Key words: Probiotic, synbiotic, depression, antidepressant, forced swimming test, complementary medicine ÖZ Amaç: Günümüzde temin edilebilen antidepresan ilaçların belirgin dezavantajları vardır; yan etkilerine ve yavaş etki etmelerine ek olarak, orta derecedeki etkinlikleri bazı kişilerde hasta uyuncunu etkileyebilir. Daha önceki literatür bilgileri probiyotiklerin antidepresan etkilere sahip olabileceğini göstermiştir. Antidepresan ilaçların terapötik dozlarının etkinliğini artırmak için tamamlayıcı tıbbın etkisinin çok önemli olduğu düşünülmektedir. Burdan hareketle, bu çalışmada içme suyuna sinbiyotik bir karışımın eklenmesinin etkisi, farklı sınıflara ait üç antidepresan ilacın uygulanmasını takiben fare depresyon modelinde değerlendirilmiştir. Gereç ve Yöntemler: Obsesif davranış ve umutsuzluğun hayvan modeli olarak misket gömme testi (MBT) ve zorunlu yüzme testi (FST) kullanılmıştır. Sinbiyotik karışım, farelerin içme suyuna (6,25x106 CFU) 14 gün boyunca uygulanmış ve testler, 7. ve 14. günlerde en düşük dozda doksepin (1 mg/ kg), venlafaksin (15 mg/kg) ve fluvoksamin (15 mg/kg) enjeksiyonundan 30 dakika sonra yapılmıştır. Bulgular: Sinbiyotik karışımın 7 gün süreyle uygulanmasından sonra, doksepin (92±5,5 s) ve venlafaksin (17,3±2,5 s) için FST’de kontrol grubuna (içme suyu) kıyasla hareketsizlik süresi azalmış, ancak fluvoksamin ile, sinbiyotik karışımın 14 gün süreyle uygulanmasından (70±7,5 s) sonra hareketsizlik süresi azalmıştır. Sinbiyotik karışımın önceden uygulanması venlafaksin için MBT test yanıtını geliştirmiş, diğer iki ilacın sonuçlarını değiştirmemiştir. Sonuç: Sinbiyotik karışımın içme suyuna eklenmesi, özellikle FST sırasında ayrı antidepresan ilaçların etkinliğini arttırmıştır. Probiyotikler, ilaca dirençli depresif bireyler için yararlı bir tamamlayıcı olabilir. Anahtar kelimeler: Probiyotik, sinbiyotik, depresyon, antidepresan, zorunlu yüzme testi, tamamlayıcı tıp *Correspondence: E-mail: [email protected], Phone: +00983137927089 ORCID-ID: orcid.org/0000-0003-3150-5581 Received: 04.02.2019, Accepted: 07.03.2019 ©Turk J Pharm Sci, Published by Galenos Publishing House. 293 294 MESRIPOUR et al. Synbiotic Mixture Augmented Antidepressant Drug Efficacy INTRODUCTION intestinal microflora such as Lactobacilli and Bifidobacteria also Probiotics are live organisms that when chronically ingested in have neurotropic effects.18 adequate amounts could induce beneficial effects in the host.1 Although drug therapy of depression is usually safe and Single strain probiotics or their combinations are useful for a effective, it is still not ideal because the latency time for variety of diseases, including gastrointestinal (GI) disorders clinical results is quite long (about 3-5 weeks) and there are such as inflammatory bowel disease, diarrhea, Irritable still concerns regarding side effects such as loss of libido Bowel syndrome (IBS), and allergies.2 This is now even being and weight gain. Additionally, there are a significant number extended to some ailments of the central nervous system of patients that do not respond well to antidepressant drugs, (CNS).3,4 Gut bacterial microorganisms have two dominant psychotherapy, and electroconvulsive therapy.19 Thus the aim of genera, Bacteroidetes and Firmicutes, while other types have the present study was to first observe the effect of a synbiotic lower abundance, for instance Proteobacteria, Actinobacteria, (probiotic + prebiotic) mixture on behavior in an animal model and Fusobacteria.5 Evidently, the brain-gut axis is a bidirectional of depression. Since it has been previously shown11-15 that the homeostatic route and so its aberration may cause important probiotics Lactobacilli and Bifidobacteria have antidepressant pathophysiological results.3 The high risk of co-existing effects in animal studies, a manufactured premixed product psychiatric symptoms such as anxiety with GI disorders, for was chosen that comprised these genus and also a prebiotic, instance IBS, provides further evidence of the importance of fructooligosaccharides. Second, in order to observe the effect this axis.6 The brain-gut axis is connected not only by complex of the synbiotic mixture on the efficacy of antidepressant systems including the vagus nerve, endocrine, immune, and drugs from different classes, subthreshold doses of doxepin humoral links but also the gut microbiota in order to maintain [a tricyclic antidepressant (TCA)], venlafaxine [a serotonin- GI stability and to connect cognitive and emotional areas of the norepinephrine reuptake inhibitor (SNRI)), and fluvoxamine (a brain with GI functions.7 selective serotonin reuptake inhibitor (SSRI)] were chosen. Major depressive disorder is the most common mood disorder, affecting 5% of the population each year.8 Several mechanisms MATERIALS AND METHODS are involved in its pathogenesis, such as altered monoaminergic Animals (serotonergic, noradrenergic, and dopaminergic) and Male Swiss mice weighing 23-26 g were housed at 21±2 ºC glutamatergic systems, increased inflammation, hypothalamic- in a 12-h light/dark cycle with the lights on in the day time 6 pituitary-adrenal (HPA) axis aberrations, and decreased am-6 pm. Tap water or the synbiotic mixture and standard 9 neuroplasticity. Probiotics have shown antidepressant food pellets were available ad libitum. For each experiment effects in animal models of depression. Species of the genus 6 mice were used and they were housed 3 per cage. Tests 10 Lactobacillus are particularly characterized as antidepressants. were performed in the behavior laboratory 24 h after the A probiotic mixture of Lactobacillus strains (L. rhamnosus and L. mice had become acclimatized to the environment. In order to helveticus) ameliorated depression by regulating corticosterone minimize the influence of circadian rhythm, all experiments 11 levels in rat pups. Likewise, chronic ingestion of a L. rhamnosus were performed between 8 am and 1 pm in the pharmacology strain (JB-1) in mice alleviated depressive behavior and caused laboratory. All animal procedures were approved by the Ethics regional alteration in GABA receptor expression and since Committee of Isfahan University of Medical Science and these changes were not observed in vagotomized mice the performed in accordance with the National Institutes of Health 12 vagus nerve was considered critical for the brain-gut axis. Guide for the Care and Use of Laboratory Animals (Ethical no: Bifidobacterium species also induce physiologic changes in IR.MUI.REC.1395.3.864). favor of antidepressants effects in animal studies; for instance, B. infantis ameliorated depressive behavior in the maternal The synbiotic mixture and drug therapy separation model.13 In a systematic review regarding the effects The synbiotic mixture comprised 109 CFU [Lactobacillus casei, L. of probiotics on depression in humans most of the studies found acidophilus, L. rhamnosus, L. bulgaricus, Bifidobacterium breve, positive results on all values of depressive symptoms, but there B. infantis, Streptococcus thermophilus, fructooligosaccharides were wide differences in the strain of probiotic, the dosing, and (a prebiotic); a product
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